Angiogenesis, the formation of new blood vessels, is the cardinal feature of virtually all malignant tumors and because of its commonality, probing tumor-induced angiogenesis and associated proteins is a viable approach to detect and treat a wide range of cancers. Angiogenesis is stimulated by integrins, a large family of transmembrane proteins that mediate dynamic linkages between extracellular adhesion molecules and the intracellular actin skeleton. Integrins are composed of two different subunits, α and β, which are non-covalently bound into αβ complexes. Particularly, the expression of αvβ3 integrin (ABI) in tumor cells undergoing angiogenesis and on the epithelium of tumor-induced neovasculature alters the interaction of cells with the extracellular matrix, thereby increasing tumorigenicity and invasiveness of cancers.
Numerous studies have shown that ABI and more than 7 other heterodimeric integrins recognize proteins and low molecular weight ligands containing RGD (arginine-glycine-aspartic acid) motifs in proteins and small peptides. Based on structural and bioactivity considerations, cyclic RGD peptide ligands are preferred as delivery vehicles of molecular probes for imaging and treating ABI-positive tumors and proliferating blood vessels. Until recently, most of the in vivo imaging studies were performed with radiopharmaceuticals because of the high sensitivity and clinical utility of nuclear imaging methods. Particularly, the use of small monoatomic radioisotopes does not generally interfere with the biodistribution and bioactivity of ligands. Therefore, once a high affinity ligand for a target receptor is identified, the radiolabeled analogue is typically used to monitor the activity, pharmacokinetics and pharmacodynamics of the drug or imaging agent. Despite these advantages, nuclear imaging is currently performed in specialized centers because of regulatory, production and handling issues associated with radiopharmaceuticals. Optical imaging is an alternative, but complementary method to interrogate molecular processes in vivo and in vitro.
Optical imaging for biomedical applications typically relies on activating chromophore systems with low energy radiation between 400 and 1500 nm wavelengths and monitoring the propagation of light in deep tissues with a charge-coupled device (CCD) camera or other point source detectors. Molecular optical imaging of diseases with molecular probes is attractive because of the flexibility to alter the detectable spectral properties of the beacons, especially in the fluorescence detection mode. The probes can be designed to target cellular and molecular processes at functional physiological concentrations. For deep tissue imaging, molecular probes that are photoactive in the near infrared (NIR) instead of visible wavelengths are preferred to minimize background tissue autofluorescence and light attenuation caused by absorption by intrinsic chromophores. In contrast to radioisotopes, the NIR antennas are usually large heteroatomic molecules that could impact the biodistribution and activity of conjugated bioactive ligands. However, previous studies have shown that conjugating small peptide carriers with NIR molecular probes successfully delivered the beacons to target proteins in vivo, and the nonspecific distribution of the conjugate in non-target tissues can be minimized by adjusting the net lipophilicity and ionic character of the conjugate.
A need, however, exists for additional compounds that can target and monitor integrin expression. In particular, a need exists for compounds that can target, monitor and/or treat a variety of integrin-mediated disorders.